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Distribution of novel and well-known poly- and perfluoroalkyl substances (PFASs) in human serum, plasma, and whole blood Somrutai Poothong, Cathrine Thomsen, Juan Antonio Padilla Sanchez, Eleni Papadopoulou, and Line Småstuen Haug Environ. Sci. Technol., Just Accepted Manuscript • DOI: 10.1021/acs.est.7b03299 • Publication Date (Web): 22 Oct 2017 Downloaded from http://pubs.acs.org on October 26, 2017

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Distribution of novel and well-known poly- and perfluoroalkyl substances (PFASs) in

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human serum, plasma, and whole blood

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Somrutai Poothong,1* Cathrine Thomsen,1 Juan Antonio Padilla-Sanchez,1 Eleni

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Papadopoulou,1 Line Småstuen Haug1

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Health, P.O. Box 4404, Nydalen, NO-0403 Oslo, Norway.

Department of Environmental Exposure and Epidemiology, Norwegian Institute of Public

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*Corresponding author:

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Somrutai Poothong

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Department of Environmental Exposure and Epidemiology, Norwegian Institute of Public

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Health, P.O. Box 4404, Nydalen, NO-0403 Oslo, Norway

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Phone number: +47 21076347

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E-mail: [email protected]

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To be submitted to – Environmental Science and Technology


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Abstract Currently, there is limited knowledge on the distribution of poly- and perfluoroalkyl

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substances (PFASs) in different blood matrices, particularly for novel PFASs such as

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polyfluoroalkyl phosphate esters (PAPs) and perfluoroalkyl phosphonates (PFPAs). To

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explore this, serum, plasma, and whole blood from 61 adults in Oslo, Norway were collected.

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The largest number of PFASs were detected in whole blood. For PAPs and PFPAs, the highest

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frequencies of detection and concentrations were observed in plasma. PAPs contributed to 8%

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of total PFASs in plasma (median, 0.81 ng mL-1). Perfluorohexylphosphonate (PFHxPA) was

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the dominant PFPA, regardless of blood matrix. The relative composition profiles of PFASs in

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blood matrices differed. For some specific PFASs such as perfluorooctanesulfonamide

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(PFOSA) and perfluorohexanoate (PFHxA), the highest concentrations were observed in

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whole blood. The PFAS concentration ratios varied between blood matrices, depending on the

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compounds. However, similar ratios were observed for 6:2 polyfluoroalkyl phosphate diester

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(6:2diPAP) as well as well-known PFASs such as perfluorooctanesulfonate (PFOS) and

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perfluorooctanoate (PFOA). Besides the determination of twenty-five PFASs in human blood,

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this study also lead to better understanding of biomonitoring data from different blood

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matrices, which is key knowledge for performing both exposure assessments and

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epidemiological studies.


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Introduction Poly- and perfluoroalkyl substances (PFASs, CnF2n+1 −R) are a broad range of

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synthetic organofluorine compounds based on two structural components, a hydrophobic

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poly- or perfluoroalkyl chain, and a hydrophilic functional group (e.g. –COOH and –SO3H).

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These unique molecules have been very useful in surfactant and polymer industries.1-2

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However, their widespread use and unique physicochemical properties have also resulted in

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their ubiquitous contamination of the environment, bioaccumulation in animals,3 and presence

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in human blood all over the world.4-7 Most studies on PFASs so far have been limited to

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perfluoroalkyl sulfonates (PFSAs, CnF2n+1SO3H) and perfluoroalkyl carboxylates (PFCAs,

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CnF2n+1COOH), particularly in human blood.8

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Associations between concentrations of some specific PFSAs and PFCAs in human

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serum or plasma and a range of health outcomes have been observed in epidemiological

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studies.9-11 Furthermore, a range of toxicological effects have been observed in animal studies

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including tumor development, hormonal effects, and immunotoxicity.12-13 Based on its

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persistence in the environment as well as the bioaccumulation and toxicological potential, use

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of perfluorooctanesulfonate (PFOS) has been banned or restricted worldwide.14-16

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Perfluorooctanoate (PFOA) has been identified as a substance of very high concern (SVHC)

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in the REACH regulation and has been banned in consumer products in Norway.17 Following

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such measures for some of the well-known PFASs, a shift towards production of short-chain

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PFSAs/PFCAs and other functional groups such as polyfluoroalkyl phosphate esters (PAPs)

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and perfluoroalkyl phosphonates (PFPAs) has occured.18-19 Previous studies have found that

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the well-known PFSAs and PFCAs accounted for only 33–85% of total extractable organic

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fluorine in whole blood of general populations.20-21 Thus, there are other PFASs in human

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blood but so far, few biomonitoring studies have assessed the exposure to for instance PFAS

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precursors and novel PFASs due to methodological limitations of chemical analyses.


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PFPAs (CnF2n+1P(O)(OH)2) are emerging PFASs and belong to the class of

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perfluoroalkyl acids (PFAAs) along with PFSAs and PFCAs. PFPAs have been detected in

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the environment, such as in surface water22 and wastewater,23 but also in indoor dust.24 Wang

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et al. recently compared PFPAs to PFSAs and PFCAs and found similarities in persistence

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and elimination potential in rainbow trout and rats.25 A limited number of studies have

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included PFPAs, but there is a particular need for data on PFPAs in the same samples as of

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PFSAs and PFCAs. Previous studies have reported that human body burden of PFASs also

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occurs through indirect exposure to PFAS precursors, such as PAPs and perfluoroalkyl

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sulfonamides (FOSAs). PAPs are surfactants possessing at least one polyfluoroalkyl tail,

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F(CF2)nCH2CH2, and are mainly used in paper food packaging.26 Biotransformation of PAPs

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into PFCAs has been observed in rats.27-28 In vivo animal experiments have also reported

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biotransformation of FOSAs to PFOS.29

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Blood is an important and favorable matrix for determining the internal dose of

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PFASs, and serum and plasma are most frequently used due to practical considerations, rather

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than favorable partitioning of PFASs. However, to back calculate PFAS concentrations in

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serum/plasma to whole blood, knowledge on the distribution of PFASs in the different blood

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matrices is crucial. Whole blood consists of cellular elements (~45%) suspended in plasma

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(liquid component, ~55%). If whole blood is allowed to clog and then centrifuged, about 30–

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50% of the volume is serum/plasma, depending on anticoagulants. If it is correct that the

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PFAS concentrations obtained in whole blood are approximately half those in serum/plasma it

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can be assumed that PFASs are distributed mainly to the serum/plasma and to a limited extent

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to the blood cells. However, as human blood is a complex mixture, also plasma and serum are

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distinct fractions of whole blood. Plasma contains fibrinogen and has a higher total protein

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content than serum, whereas serum has a higher concentration of some important protein and

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platelet.30 In addition, different PFASs are known to have different physicochemical


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properties and different binding affinities to blood.31 Limiting the analyses of PFASs to

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serum/plasma might exclude the possible amount present in blood cells, and thus

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underestimate the body burden. It should be emphasized that determination of PFASs in both

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human serum, plasma, and whole blood from the same individual has seldom been carried out.

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This is particularly true for novel PFASs, while some few studies have emphasized this aspect

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for some well-known PFASs (e.g. PFOS, PFOA, perfluorohexanesulfonate (PFHxS),

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perfluorononanoate (PFNA), and perfluorooctanesulfonamide (PFOSA)).32-34 Some studies

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have only considered the partitioning between plasma and whole blood,32, 34-35 and/or included

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only small and specific groups of the population (e.g. occupational, maternal).32-34 However,

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knowledge on distributions between different blood matrices is important when performing

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risk assessments, and can be of high importance when evaluating the possibilities of reverse

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causations in epidemiological studies.

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The aims of the present study were to assess the presence, concentrations, composition profiles, and correlations of various PFASs in whole blood, plasma and serum in a study

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group of the general adult population. Further, correlations and distribution ratios between

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different blood matrices were determined for each of the PFASs. Apart from measuring the

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well-known PFASs such as PFSAs, PFCAs, and FOSAs, this study also included novel

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PFASs such as PAPs and PFPAs for which this information is lacking entirely.


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Materials and methods

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Study population

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During winter 2013–2014, 61 women and men living in the Oslo area, Norway were

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enrolled in the Advanced Tools for Exposure Assessment and Biomonitoring (A-TEAM)

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project,36 where serum, plasma, and whole blood were obtained. The participants comprised

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45 women and 16 men (~75% women) between the age of 20 and 66 years old, with a median

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age of 41 years. The Regional Committees for Medical and Health Research Ethics in Norway

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(2013/1269) approved the sampling campaign of the A-TEAM project. In addition, all

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participants gave a written consent before participating.

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Sample collection Blood samples were drawn from a single venipuncture site. Whole blood samples were

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collected in K2-ethylenediaminetetraacetic acid (EDTA) anticoagulant vacutainer tubes

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(Becton, Dickinson and Company, Plymouth, UK). After a fraction of the whole blood was

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transferred to a 2 mL polypropylene tube, the remaining blood in the EDTA vacutainer tube

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was left to clot for one hour, centrifuged for 15 min at 2200-2500 rpm and then plasma was

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transferred to a PP bottle. Vacutainer tubes without anticoagulant were used to collect blood

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to obtain serum from the participants. The blood in the vacutainer tube without anticoagulant

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was left to clot for one hour, centrifuged for 15 min at 2200-2500 rpm and then serum was

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transferred to a PP bottle. All samples were stored at -20°C until further analysis.

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Chemicals and standards

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The twenty-five PFASs included in this study were 6:2 polyfluoroalkyl phosphate monoester

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(6:2PAP), 8:2 polyfluoroalkyl phosphate monoester (8:2PAP), 6:2 polyfluoroalkyl phosphate

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diester (6:2diPAP), 8:2 polyfluoroalkyl phosphate diester (8:2diPAP),


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perfluorohexylphosphonate (PFHxPA), perfluorooctylphosphonate (PFOPA),

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perfluorodecylphosphonate (PFDPA), perfluorobutanesulfonate (PFBS), PFHxS,

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perfluoroheptanesulfonate (PFHpS), PFOS, perfluorodecanesulfonate (PFDS),

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perfluoropentanoate (PFPeA), perfluorohexanoate (PFHxA), perfluoroheptanoate (PFHpA),

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PFOA, PFNA, perfluorodecanoate (PFDA), perfluoroundecanoate (PFUnDA),

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perfluorododecanoate (PFDoDA), perfluorotridecanoate (PFTrDA), perfluorotetradecanoate

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(PFTeDA), PFOSA, N-methyl perfluorooctanesulfonamide (MeFOSA), and N-ethyl

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perfluorooctanesulfonamide (EtFOSA). Details on the twenty-five native PFASs and eleven

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isotope-labeled internal standards are given in Table S1 of supporting information. Since

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PFSAs and PFCAs have been detected in human blood worldwide, but analyses of their

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precursors have seldom been performed. Thus, this study included PFSA and PFCA

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precursors, which were FOSAs and PAPs, respectively. In contrast, no studies have so far

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detected PFPAs in human blood, and therefore only PFPAs were selected in this study, not

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their precursors compounds (i.e. PFPiAs).

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Blood analysis PFAS concentrations in serum, plasma, and whole blood samples were determined

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using an established method by Poothong et al.37 Briefly, 50 µL of blood (serum, plasma, or

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whole blood) was added to a 2 mL centrifuge tube, and then 90 µL of a 5 ng mL-1 internal

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standard solution and 90 µL of methanol were added. To precipitate the proteins, the sample

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tubes were mixed on a whirl mixer and centrifuged for 40 min at 14000 rpm at 20°C. The

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supernatant was transferred to a 250 µL polypropylene vial, and then 80 µL of the sample was

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injected in an online-SPE-UHPLC-MS/MS system.

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Quality assurance/quality control


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Duplicate matrix-matched calibration standards were prepared in twelve different

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concentrations in the range 0.006–45 ng mL-1 blood. Newborn calf serum (Invitrogen, Oslo,

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Norway), calf plasma, and calf whole blood (Lampire Biological labs, Pipersville, USA) were

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used for the preparation of the matrix-matched calibration standards for serum, plasma, and

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whole blood analysis, respectively. The matrix-matched calibration standards were injected

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before and after the samples to ensure linearity in instrument response during the analysis and

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for monitoring possible drifts in the sensitivity. Quantification was performed using

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concentration-weighted (1/concentration) linear regression. For quantification of PFOS, the

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total area of linear and branched isomers was integrated. Three solvent procedure blanks and

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three non-spiked calf serum, calf plasma or calf whole blood were included in the analysis to

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monitor the PFASs background levels. To assure high quality of the determinations, in-house

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quality control samples of human plasma and whole blood as well as human serum samples

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from an interlaboratory comparison study (Arctic Monitoring and Assessment Programme,

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AMAP) (n = 3) were analyzed along with the human serum, plasma, and whole blood

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samples. The results of the serum, plasma, and whole blood quality control samples were

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similar to the previous results of the application in method developments (lower than 15%

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relative standard deviations, RSD).37 More details on the quality assurance and quality control

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including assessment of method accuracy, repeatability, precision, and method detection

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limits can be found in Poothong et al.37

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Data analysis To calculate mean and median concentrations, concentrations below the method

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detection limits (MDLs) were replaced with their MDLs divided by the square root of two

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(MDL/√2), while values between the MDLs and method quantification limits (MQLs) were

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used unaltered. This approach was also employed when evaluating the composition profiles


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and correlations in the matrices. A Mann-Whitney U-test was used to assess differences in

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PFAS concentrations between genders and to compare current levels with concentrations

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reported in another similar study from Norway. Statistically significant differences in PFAS

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concentrations with respect to age-tertiles were evaluated using a Kruskal-Wallis test.

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Correlations between compounds were evaluated with Spearman's rank correlation coefficient

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(rho) and tested for significance.

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To evaluate the distribution ratio of PFASs between different blood matrices, only

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paired samples from individuals with quantifiable concentrations (>MDL) in serum, plasma,

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and whole blood were included. Since the PFAS concentration ratios between serum, plasma,

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and whole blood are expected to be similar in all individuals, correlations between PFAS

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concentrations in pairs of blood matrices were evaluated using Pearson correlation (pairwise

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comparison) and tested for significance. A Wilcoxon signed ranks test was used for assessing

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the statistically significant differences of PFASs in different blood matrices.

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P-values < 0.05 were considered significant in all statistical tests. A Shapiro-Wilk W

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test was used to test the data for normality. Statistical analyses were performed by using the

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SPSS 23 software, except heat-map correlation plots which were made using the corrgram

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package in R version 3.2.2.38, 39


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Results and discussion

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Detection frequencies and concentrations of PFASs in serum, plasma, and whole blood

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Twenty-one of the twenty-five PFASs were detected in blood samples, although the

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detection frequencies varied depending on the compounds and the blood matrices. PFHxS,

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PFHpS, PFOS, PFOA, and PFNA were detected in all serum (n=61), plasma (n=59), and

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whole blood (n=58) samples. Approximately 50–100% of all blood matrices had detectable

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concentrations of 6:2diPAP, PFHxPA, PFBS, PFDS, PFDA, PFUnDA, PFDoDA, PFTrDA,

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and PFOSA, while the detection frequency was more than 50% in some of the blood matrices

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for 6:2PAP, PFHxA, and PFTeDA as shown in Table 1. No samples had PFDPA, PFPeA,

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MeFOSA, and EtFOSA levels above their respective MDLs (0.0036–0.09 ng mL-1) (Table

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S2), while 8:2diPAP, PFHpA were detected in all matrices but in less than 50% of the

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samples.

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PAPs

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Among the PAPs, 6:2diPAP had the highest detection frequency in all blood matrices

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(49–98%, plasma>whole blood>serum). 6:2PAP and 8:2diPAP were observed in 3–73% and

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21–30% of the samples in all blood matrices, respectively, whereas 8:2PAP was detected only

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in 5% of the whole blood samples. Interestingly, 6:2PAP was present in 73% of the plasma

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samples while it has never been reported in human blood before. Very few studies have

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previously determined the concentrations of PAPs in human blood, and most of them assessed

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only serum. Detection frequencies of serum diPAPs in the present study were comparable to

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other studies of PAPs in serum.6, 40 The serum concentrations of 6:2PAP, 6:2diPAP, and

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8:2diPAP in this present study were in range of PFPAs of equal perfluorocarbon chain length.47 Assuming similar bioaccumulation

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potentials in humans, the low levels of PFPAs in blood samples might be due to a fast

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elimination rate in human body. However, to obtain more knowledge on this, assessments of

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human exposure pathways for PAPs and PFPAs are needed. In addition, the relatively low


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levels of PAPs and PFPAs observed in this study indicates that there is still a large amount of

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organofluorine compounds in blood which are unidentified.21

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PFSAs, PFCAs, and FOSAs Interestingly, PFHxA was detected in 100% of the whole blood samples while it was

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not detected in any of the other blood matrices. This suggests that whole blood is the only

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suitable blood matrix for determination of PFHxA, and that the exposure to PFHxA is

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overlooked when assessing serum or plasma. These findings are in line with several recent

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studies where PFHxA was not detected, or found in very few samples when assessing

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serum/plasma.6, 42, 48-49

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PFOSA was the only FOSA detected in any of the blood matrices (71–100%, whole

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blood>serum>plasma), where the concentrations in whole blood were approximately one

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order of magnitude higher than the ones in serum and plasma. The reason for detecting

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PFOSA and PFHxA in higher frequencies and concentrations in whole blood compared to

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serum and plasma is likely due to binding of the compounds to blood cells.

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To assess time trends of PFSA s and PFCAs, levels from this study were compared to

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a previous Norwegian study where samples were collected in 2007–2008 (41 women, age 28–

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46, median 36).45 A significant decrease in the median PFOS concentration of around 35%

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was observed (Figure S1). Surprisingly, no statistical significant change was observed for

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PFOA (Mann-Whitney U test, p>0.05), even though PFOS and PFOA have comparable

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elimination half-lives (PFOS: 4.8 years, PFOA: 3.5 years).50 Thus, either the exposure to

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PFOA has not changed to the same extent as PFOS, or the direct PFOA exposure has

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decreased but the indirect exposure through the biotransformation of precursor compounds to

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PFOA has substantially increased. In addition, for PFUnDA no statistical change in the serum

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concentrations was observed between the 2007/2008 study and the recent study. On the other


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hand, increasing PFAS concentrations were observed between 2007/2008 and 2013/2014 for

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PFHpS (74%), PFHxS (53%), PFDA (45%), and PFNA (31%). Increasing concentrations of

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some long-chain PFCAs such as PFNA, PFDA, and PFUnDA have also been reported in

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recent time trend studies in Danmark,51 Sweden,41, 52 and Japan.53 PAPs are metabolized into

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long-chain PFCAs.27, 43 Thus despite direct exposure, the increasing levels of these long-chain

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PFCAs might also relate to the indirect exposure from PAPs, which are still used in consumer

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products.

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Several studies have determined PFSAs, PFCAs, and FOSAs in human blood. PFOS

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serum concentrations in the present study (median, 5.2 ng mL-1) were comparable to studies

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from Sweden (2012)41 and Denmark (2008-2013),51 while studies in Australia (2010-2011)54

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and the U.S. (2009)40 found PFOS concentrations in serum which were two times higher than

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in this study. On the other hand, the PFOS median concentration reported in a study from

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China (2009) was approximately half of that of the present study.42 The median serum

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concentration of PFOA was 1.9 ng mL-1, which is similar to recent studies from the U.S.40 and

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Denmark,51 while it was two times lower than in Australia.54 This study found similar median

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serum concentrations of PFNA (0.9 ng mL-1), PFDA (0.4 ng mL-1), and PFUnDA (0.4 ng mL-

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1

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levels varied among the studies.

) as studies from the U.S.,40 Australia,54 Sweden,41 Denmark,51 and China,42 while PFHxS

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PFAS profiles in serum, plasma, and whole blood

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The relative composition profiles of PFASs in serum, plasma, and whole blood was

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evaluated for PFASs with detection frequencies above 50% in each blood matrix (Table 1).

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Total PFAS concentrations (ΣPFASs) were 10, 10, and 6.3 ng mL-1 in serum, plasma, and

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whole blood, respectively. Significant difference of PFAS concentrations between ages and

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genders were assessed. In whole blood, PFHxS, PFHpS, and PFOS concentrations in women


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were significantly lower than in men (Mann−Whitney U test, p ≤ 0.005, 2-tailed) (Table S3),

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which is possibly linked to menstruation. Based on a pharmacokinetic model, menstruation

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accounted for 30% of the difference in PFOS elimination between genders.55 No statistically

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significant difference was observed between genders in the other compounds.

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The oldest age group (age-tertiles, 45) had significantly higher PFOA,

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PFNA, PFDA, PFUnDA, PFTeDA, PFDS, and PFOSA concentrations in blood compared to

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the other two age groups (Kruskal-Wallis test, p ≤ 0.05), while this was not the case for the

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other compounds. The median relative PFAS compositions (ng mL-1) in serum, plasma, and whole blood

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were all dominated by PFOS, followed by PFOA (Figure 1). The sum of PFOA and PFOS

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contributed to 60–70% of the total PFAS concentrations. The contribution of PFPAs and

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PAPs to the total PFAS concentrations in human blood were relatively low, and thus the

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major fluorinated contaminants measured in this study in human blood are still PFSAs and

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PFCAs. The PFAS composition profiles in serum and plasma were similar, with the

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proportion of PFOS (48–51%) > PFOA (16-19%) > PFNA ≈ PFHxS (7–9%) > PFUnDA ≈

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PFDA (3–4%) > PFHpS ≈ PFHxPA (2–3%) > PFTrDA ≈ PFDoDA ≈ PFDS ≈ PFBS ≈

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PFOSA (1%). The 6:2diPAP contributed to 1% in plasma. Also the low detection frequency

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PAP congener, 6:2PAP contributed to a greater percentage in plasma by 7%. Consequently, in

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this study plasma proved to be a relevant matrix to quantifying PAPs and PFPAs in human

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blood.

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The relative composition of various PFASs in whole blood differed from serum and

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plasma. PFHxA was only detected in whole blood, where it accounted for as much as 10% of

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the total PFAS concentrations. Thus the composition profile of PFASs in whole blood was

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PFOS (45%) > PFOA (15%) > PFHxA (10%) > PFNA ≈ PFHxS (6–7%) > PFUnDA ≈ PFDA

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≈ PFTrDA ≈ PFOSA (2–3%) > PFTeDA ≈ PFDoDA ≈ PFDS ≈ PFHpS ≈ PFBS ≈ PFHxPA ≈


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6:2diPAP (1%). Interestingly, whole blood was the matrix where the largest number of PFASs

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was detected (16 PFASs), while serum and plasma have been the most frequently used

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matrices in biomonitoring studies. In accordance with these differing PFAS profiles in serum,

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plasma, and whole blood, epidemiological studies need to be taken into consideration when

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associating PFASs levels in the blood with the health outcome.

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Correlations between PFASs within the same blood matrix Correlations between different PFASs (detection frequency >50%) within the same

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blood matrix were evaluated based on Spearman's rank correlation coefficients, and are

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presented in Figure 2. Both weak positive and negative correlations were observed between

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PAPs, as well as PFHxA with the other PFASs. However, weak but significant correlations

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were observed between 6:2diPAP and PFHxA in whole blood (rs = 0.38, p

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